The morphogenesis of the organ of Corti provides an excellent model to study pattern formation, cell fate determination and coordinated control of cell proliferation and differentiation. Recent advance in genetics has allowed the identification of pathways involved in cell cycle regulation and in selection of hair cell vs. supporting cell fate. However, pathways required for specification of the organ of Corti remain elusive. Our studies have shown that the closest mouse homology of Drosophila proneural gene atonal, Math 1, appears not o be required for the establishment of the sensory primordium in the cochlea while it is necessary and sufficient for the differentiation of hair cells. Based on our preliminary data and observations by others, we hypothesize that Mathi is not required for the specification of the sensory primordium in the cochlea. In this )proposal, we will first test our hypothesis and then use candidate gene cloning approach to explore upstream )pathways involved in the morphogenesis of the organ of Corti. In our Specific Aim I, we will provide direct evidence that the sensory primordium is a prosensory domain within which all the cells are competent to become hair cells, then confirm that Math 1 is not required for the establishment of this prosensory domain that will give rise to hair cells and supporting cells of the organ of Corti. In Specific Aim II, we will use candidate ;gene cloning approach to identify upstream factors for Math I that are involved in specification of the sensory primordium. Preliminary, we have isolated a gene whose expression pattern is consistent with an upstream role for Math 1. Functional studies will be carried out to determine the exact role of isolated genes.The accomplishment of this proposal will not only further dissect the pathways regulating the morphogenesis of organ of Corti and provide general tools to isolate stage- and cell type-specific genes, but also provide an excellent model for comparative study of molecular mechanisms involved in organogenesis during evolution. It might also provide vital information for stimulating hair cell regeneration in mammals.